Fetal hypoxia is a major clinically relevant stressor representing a threat to fetal survival and well- being. However, the fetus has the remarkable ability to adapt to conditions of chronic or long-term hypoxia (LTH) over the course of gestation and the fetal HPA axis represents an important element in the adaptation to LTH. Our laboratory has developed a model of LTH in which pregnant ewes are maintained at high altitude (3,820 m) resulting in a sustained, moderate hypoxic state from day 30 of gestation onward. We have shown that the HPA axis of fetal sheep undergoes significant adaptation in response to LTH. This adaptation includes enhanced anterior pituitary processing of POMC to ACTH1-39, increased basal plasma ACTH1-39 and, in response to a secondary stressor, enhanced ACTH1-39 release. The adrenal cortex of the LTH fetus also adapts in response to LTH including a reduced expression of key steroidogenic enzymes (CYP17 and CYP11A1). Cumulatively, these seemingly contradictory adaptations in the hypothalamo-pituitary vs. adrenocortical components of the HPA axis result in maintenance of basal cortisol levels yet greater cortisol production in response to a secondary stressor in the LTH fetus. While the increased function observed at the level of the hypothalamic-pituitary component in the LTH fetus is consistent with the known stimulatory actions of short-term hypoxia on fetal HPA function, the adaptive changes observed at the level of the adrenal cortex seem paradoxical. Thus, we hypothesize that LTH has invoked a mechanism(s) that prevents premature maturation of the adrenal cortex in the face of elevated basal ACTH1-39 yet allows increased cortisol production in response to a life-threatening secondary stressors. These adaptations in the HPA axis in response to LTH likely aid in the survival of the compromised LTH fetus while preventing preterm delivery in response to the hypoxic condition. The mechanisms mediating adaptation of the HPA axis in response to LTH remain to be elucidated. Our novel preliminary data demonstrate 1) enhanced leptin expression in white adipose tissue and elevated plasma leptin concentrations 2) increased leptin receptor expression in the adrenal gland of the late gestation LTH sheep fetus and 3) new preliminary data clearly showing the dramatic effects of a leptin antagonist at the level of the adrenal cortex but not at the hypothalamic-pituitary level. Thus, leptin appears to be a key agent preventing the adrenal cortex from responding to the elevated basal ACTH1-39 observed in the LTH fetus. In adults, leptin is a hypoxia-inducible gene and has clearly been demonstrated to alter HPA function. The proposed studies will test the overall hypothesis that the enhanced leptin production observed in the LTH fetus plays a key role in regulating the dramatic changes in the HPA axis that allow the fetus to acclimatize to the stress of long-term hypoxia yet retain the ability to respond to acute stress. PUBLIC HEALTH RELEVANCE: The proposed studies are critical to our basic understanding of fetal adaptive mechanisms to chronic stress. Results from these studies will also have great potential for understanding the physiologic basis for clinical problems such as delayed development, intrauterine growth retardation, disease in the fetus and newborn, prenatal programming of the fetus to develop disease as an adult, and occult diseases that occur at high altitude.